Estrogen receptor-positive (ER+), hormone-dependent breast cancers initially respond to endocrine therapy However, many of these tumors develop drug resistance and progress, with more patients dying from ER+ breast cancer than all other breast cancer types combined. For the majority of these cancers, mechanisms of escape from antiestrogens remain to be discovered. During the current award period, we have shown that activation of the phosphatidylinositol-3 kinase (PI3K) pathway can promote resistance to endocrine therapy though demonstration of this mechanism awaits further confirmation in the clinic. The PI3K pathway is overall the most frequently altered oncogenic pathway in breast cancer. Mutations in PIK3CA, the gene encoding the p i 10a catalytic subunit of PI3K, are the most common somatic alterations of this pathway in breast cancer. These mutations confer increased PIP3-forming catalytic activity and induce growth factor- and anchorage- independent growth, resistance to anoikis, and drug resistance. Small molecule pan-PI3K inhibitors that bind reversibly to the ATP pocket of p110 have completed phase I trials. Some clinical studies have already suggested that ER+/PIK3CA mutant tumors exhibit a lower response to antiestrogens compared to ER+/PIK3CA wild-type tumors. Thus, we hypothesize that antiestrogens in combination with a PI3K inhibitor will be more effective against ER+/PIK3CA mutant breast cancers compared to the antiestrogen alone. In addition, breast cancers that do not respond to the combination will contain somatic alterations causally associated with drug resistance. To test these hypotheses, we propose the following aims: Aim 1: To determine the rate of pathological complete response in patients with ER+/HER2- breast cancer treated with the aromatase inhibitor letrozole and the pan-PI3K inhibitor BKM120 Aim 2: To identify molecular alterations potentially associated with drug resistance in breast cancers after neoadjuvant therapy with letrozole plus BKM120 Aim 3: To determine whether molecular alterations identified in post-treatment residual cancers are causally associated with resistance to endocrine therapy and inhibition of PISK RELEVANCE (See instructions): Positive results from the trial with the combination of letrozole and the PISK inhibitor (Aim 1) will identify a rational treatment option for patients with ER+/PIKSCA mutant breast cancer that does not include chemotherapy. Results from Aims 2 and 3 will identify novel mechanisms of resistance to estrogen deprivation the PISK inhibitor. These mechanisms, in turn, may represent new molecular targets that can be the focus of future drug discovery and/or clinical investigation in breast and other PI3K-depent cancers.